[en] Myelomonocytic and monocytic acute myeloid leukemia (AML) subtypes are intrinsically resistant to venetoclax-based regimens. Identifying targetable vulnerabilities would limit resistance and relapse. We previously documented the synergism of venetoclax and cardiac glycoside (CG) combination in AML. Despite preclinical evidence, the repurposing of cardiac glycosides (CGs) in cancer therapy remained unsuccessful due to a lack of predictive biomarkers. We report that the ex vivo response of AML patient blasts and the in vitro sensitivity of established cell lines to the hemi-synthetic CG UNBS1450 correlates with the ATPase Na+/K+ transporting subunit alpha 1 (ATP1A1)/BCL2 like 1 (BCL2L1) expression ratio. Publicly available AML datasets identify myelomonocytic/monocytic differentiation as the most robust prognostic feature, along with core-binding factor subunit beta (CBFB), lysine methyltransferase 2A (KMT2A) rearrangements, and missense Fms-related receptor tyrosine kinase 3 (FLT3) mutations. Mechanistically, BCL2L1 protects from cell death commitment induced by the CG-mediated stepwise triggering of ionic perturbation, protein synthesis inhibition, and MCL1 downregulation. In vivo, CGs showed an overall tolerable profile while impacting tumor growth with an effect ranging from tumor growth inhibition to regression. These findings suggest a predictive marker for CG repurposing in specific AML subtypes.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Cerella, Claudia ; Laboratoire de Biologie Moléculaire et Cellulaire du Cancer (LBMCC), Fondation Recherche sur le Cancer et les Maladies du Sang, Pavillon 2, 6A rue Barblé, L-1210, Luxembourg, Luxembourg
Gajulapalli, Sruthi Reddy ; Research Institute of Pharmaceutical Sciences & Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea
Lorant, Anne; Laboratoire de Biologie Moléculaire et Cellulaire du Cancer (LBMCC), Fondation Recherche sur le Cancer et les Maladies du Sang, Pavillon 2, 6A rue Barblé, L-1210, Luxembourg, Luxembourg
GERARD, Déborah ; University of Luxembourg ; Laboratoire de Biologie Moléculaire et Cellulaire du Cancer (LBMCC), Fondation Recherche sur le Cancer et les Maladies du Sang, Pavillon 2, 6A rue Barblé, L-1210, Luxembourg, Luxembourg
Muller, Florian; Laboratoire de Biologie Moléculaire et Cellulaire du Cancer (LBMCC), Fondation Recherche sur le Cancer et les Maladies du Sang, Pavillon 2, 6A rue Barblé, L-1210, Luxembourg, Luxembourg
Lee, Yejin; Research Institute of Pharmaceutical Sciences & Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea
Kim, Kyung Rok; Research Institute of Pharmaceutical Sciences & Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea
Han, Byung Woo; Research Institute of Pharmaceutical Sciences & Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea
Christov, Christo; University of Lorraine, Service Commun de Microscopie, Nancy, France
Récher, Christian; Cancer Research Center of Toulouse, UMR 1037 INSERM/ Université Toulouse III-Paul Sabatier, 2 avenue Hubert Curien, Oncopôle, 31037, Toulouse, France
Sarry, Jean-Emmanuel ; Cancer Research Center of Toulouse, UMR 1037 INSERM/ Université Toulouse III-Paul Sabatier, 2 avenue Hubert Curien, Oncopôle, 31037, Toulouse, France
Dicato, Mario; Laboratoire de Biologie Moléculaire et Cellulaire du Cancer (LBMCC), Fondation Recherche sur le Cancer et les Maladies du Sang, Pavillon 2, 6A rue Barblé, L-1210, Luxembourg, Luxembourg
Diederich, Marc ; Research Institute of Pharmaceutical Sciences & Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea. marcdiederich@snu.ac.kr
LBMCC: “Recherche Cancer et Sang” foundation, the “Recherches Scientifiques Luxembourg”, the “Een Häerz fir kriibskrank Kanner”, the Action LIONS “Vaincre le Cancer” and Télévie Luxembourg. CC acknowledges support from the “Fondation Gustave et Simone Prévot” (Geneva, Switzerland). SNU to MDie: National Research Foundation (NRF) [Grant Number 370C-20220063]; MEST of Korea for Tumor Microenvironment Global Core Research Center (GCRC) [Grant Number 2011-0030001]; Brain Korea (BK21) PLUS program and Creative-Pioneering Researchers Program at Seoul National University [Funding number: 370C-20160062]. SRG was supported by a grant for the “Graduate Scholarship for Excellent Foreign Students” program. SNU to BWH: This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (grant number: 2019R1A2C1090251 and RS-2023-00218543) and by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HP23C0102).
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